Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to characterize the effects of two new adenosine A2 agonists, 2-(p-(2-carboxyethyl)phenethyl amino)-5'-N-ethylcarboxamidoadenosine (CGS-21680) and N6-(2(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)-adenosine (DPMA), on erythropoietin (EPO) production in vivo and in vitro. Intravenous injections of CGS-21680 (100 to 500 nmol/kg mouse/day) and DPMA (50 to 500 nmol/kg mouse/day) for 4 days produced significant increases in serum levels of EPO in exhypoxic polycythemic mice. CGS-21680 (10(-7) to 10(-6) mol/L) and DPMA (10(-8) to 10(-5) mol/L) also produced significant increases in medium levels of EPO in a cloned EPO-producing Hep3B hepatocellular carcinoma cell line after 18 hours of incubation in 1% O2. Both compounds also increased cellular cAMP levels significantly in a dose-dependent manner after 1 hour of incubation. A2 receptor binding assays with tritiated CGS-21680 revealed a single type of adenosine receptor binding site on Hep3B cell membranes with a dissociation constant of 132.9 nmol/L and a binding capacity of 270.6 fmol/mg protein. The Ki competition binding values versus tritiated CGS-21680 were 217 nmol/L for CGS-21680 and 86.8 nmol/L for DPMA. These results indicate that adenosine A2 receptor activation amplifies EPO production in response to hypoxia, both in vivo and in vitro.
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PMID:Enhancement of erythropoietin production by selective adenosine A2 receptor agonists in response to hypoxia. 766 79

The human hepatoma cell line, Hep 3B, produces biologically active erythropoietin (Epo) in response to normal physiologic stimuli and thus provides a model system for the study of Epo regulation. The addition of phorbol 12-myristate 13-acetate (PMA) to Hep 3B cells subsequently grown under hypoxic conditions resulted in a dose-dependent inhibition of hypoxia-induced Epo production by as much as 95 +/- 1% with half-maximal inhibition at 8 ng/mL. By Northern blot analysis, Epo mRNA levels were correspondingly decreased after treatment with PMA. Direct measurement of both membrane and cytosolic protein kinase C activity in Hep 3B cells following treatment with PMA demonstrated a biphasic response as a function of time. Membrane-associated protein kinase C activity initially increased but subsequently decreased to baseline levels by 12 hours. The PMA-induced inhibition of hypoxia-induced Epo production was shown to occur as early as 3 hours after PMA addition, suggesting that the initial activation, rather than the subsequent decrease in protein kinase C activity, is of primary importance. The relative specificity of the PMA-induced inhibition of Epo production was demonstrated by 1) the finding that overall protein and RNA synthesis were not similarly decreased as measured by 3H-leucine and 3H-uridine pulse labeling studies and 2) the observation that the biologically inactive phorbol ester, 4 alpha-phorbol didecanoate, failed to have any effect on hypoxia-induced Epo production. In addition, the synthetic analog of diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG) and the calcium ionophore, A23187, inhibited hypoxia-induced Epo production up to 85 +/- 3% and 82 +/- 4%, respectively, in a dose-dependent manner. Taken together, these findings suggest that hypoxia-induced Epo production may be negatively regulated by activators of a protein kinase C-mediated pathway.
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PMID:Modulators of protein kinase C inhibit hypoxia-induced erythropoietin production. 753 Feb 14

Erythrocytosis is occasionally observed in patients with hepatocellular carcinoma (HCC). The pathogenesis of the phenomenon remains uncertain. It has been speculated that tumors produce erythropoietin (Epo), and several studies on the Epo in tumor tissues have been reported. Using a sensitive enzyme linked immunosorbent assay, we measured the serum Epo concentration in 92 HCC patients and 30 liver cirrhosis (LC) patients. The levels of Epo in normal subjects, HCC patients and LC patients were 10.5 +/- 4.1 (mean +/- SD, mU/ml), 55.6 +/- 218.0 and 18.4 +/- 19.4, respectively. Some patients with high Epo values had low levels of hemoglobin (Hb), and a scatter-gram of the two parameters was similar to that in iron deficiency anemia. In patients whose Hb levels were more than 12 g/dl, we found Epo levels of 15.0 +/- 8.8 (mean +/- SD mU/ml) and 10.3 +/- 7.7 in HCC and LC, respectively. Epo values in HCC were significantly higher than those of normal subjects (P < 0.001) and LC patients (P < 0.05), and 18.2% (10/55) had concentrations above the upper limit of the normal range. The increase was not, however, a marked one. In conclusion, as the incidence of erythrocytosis was low (2.2%) in HCC patients, the high Epo values in some patients could be related to the abnormal production of Epo by HCC.
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PMID:Serum erythropoietin measurements by a one-step sandwich enzyme linked immunosorbent assay in patients with hepatocellular carcinoma and liver cirrhosis. 769 89

Patients with hepatocellular carcinoma sometimes have erythrocytosis and high plasma erythropoietin levels. However, previous studies have not revealed direct evidence that the carcinoma cells produce the erythropoietin. To address this question, we carried out light and electron microscopic immunohistochemical studies, using a human erythropoietin antibody to the liver in three male patients with hepatocellular carcinoma and erythrocytosis. alpha-Feto-protein localization was also examined in serial liver sections by light microscopic immunohistochemistry with an antibody to alpha-fetoprotein. All three patients demonstrated high hemoglobin levels (16.7, 17.6 and 18.1 gm/dl) and high plasma erythropoietin levels (227, 266 and 280 mU/ml). In one patient the plasma erythropoietin level in the hepatic vein was significantly higher than that in the hepatic artery. The levels of plasma erythropoietin, as well as such tumor markers for hepatocellular carcinoma as serum alpha-fetoprotein and plasma des-gamma-carboxyprothrombin, were significantly reduced after treatment with an anticancer drug, cisplatin. Light microscopic immunohistochemistry showed that erythropoietin was definitely present in the cytoplasm of the hepatocellular carcinoma cells, but not in normal hepatocytes around the carcinoma lesion or in other nonparenchymal cells such as vascular endothelial cells and Kupffer cells. In electron microscopic immunohistochemistry, reaction products for erythropoietin were revealed in the cisternae of the endoplasmic reticulum in the carcinoma cells, suggesting the production of erythropoietin by these cells. Light microscopic immunohistochemistry showed that alpha-fetoprotein was localized in the hepatocellular carcinoma cells that were erythropoietin positive in the serial sections. These findings indicated that hepatocellular carcinoma cells produced erythropoietin as well as alpha-fetoprotein in these cases, leading to the complication of erythrocytosis.
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PMID:Erythropoietin production in hepatocellular carcinoma cells associated with polycythemia: immunohistochemical evidence. 769 95

The gene regulatory functions of the human IL-2 receptor (IL-2R) were reconstituted in transiently transfected hepatoma cells. The combination of IL-2R beta and -gamma mediated a strong stimulation via the cytokine response element of the alpha 1-acid glycoprotein gene and the hematopoietin receptor response element, but none via the IL-6 response element or the sis-inducible element. IL-2R alpha enhanced 10-fold the sensitivity of the IL-2R beta.gamma complex to respond to IL-2 or IL-15, but did not modify the specificity or the magnitude of maximal gene regulation. A homodimerizing chimeric receptor G-CSFR-IL-2R beta could mimic the IL-2R action. The IL-2R-mediated gene regulation was similar to that seen with receptors for IL-4 and IL-7, but differed from that for IL-6 type cytokines, thrombopoietin, erythropoietin, and growth hormone. The activation of STAT proteins by the IL-2R was assessed in transfected L-cells and COS-1 cells. Although IL-2R subunits were highly expressed in these cells, no STAT protein activation was detectable. Transient overexpression of JAK3 was unable to change the signaling specificity of the hematopoietin receptors in rat hepatoma, L-, and COS cells, but established a prominent activation of the IL-6 response elements by the IL-2R and IL-4R in HepG2 cells. The data support the model that the IL-2R and related hematopoietin receptors produce at least two separate signals which control gene expression.
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PMID:The action of interleukin-2 receptor subunits defines a new type of signaling mechanism for hematopoietin receptors in hepatic cells and fibroblasts. 771 38

We have previously identified a cytosolic protein, erythropoietin RNA binding protein (ERBP), which is up-regulated in certain tissues in response to hypoxia. To further characterize the interaction of ERBP and erythropoietin (EPO) mRNA, we have examined the role of reduction-oxidation in the EPO mRNA binding mechanism of ERBP isolated from human hepatoma cells (Hep3B). Reducing agents dithiothreitol (DTT) and 2-mercaptoethanol (2-ME) increased ERBP binding activity in a concentration-dependent manner, whereas the oxidizing agent, diamide, abolished ERBP binding activity. In addition, treatment of Hep3B cell lysates with the irreversible sulfhydryl alkylating agent N-ethylmaleimide resulted in inhibition of the EPO mRNA-ERBP complex. Taken together, these findings suggest that sulfhydryl groups may play a role in vivo in the regulation of EPO production through the modulation of ERBP binding activity.
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PMID:Changes in redox affect the activity of erythropoietin RNA binding protein. 786 12

The effects of interferon-gamma (IFN-gamma), alone and in combination with IL-1, IL-6 and tumour necrosis factor-alpha (TNF-alpha), on in vitro erythropoietin (Epo) production by the human hepatoma Hep3B cell line were evaluated. The addition of IFN-gamma to either unstimulated or cobalt chloride (CoCl2)-treated Hep3B cells resulted in a dose-dependent inhibition of Epo release in the medium by as much as 70% at 1000 U/ml. Half-maximal inhibition was observed at around 50 U/ml. According to previous observations, IL-6 had a stimulatory effect on Epo production by CoCl2-treated Hep3B cells; however, the simultaneous addition of IFN-gamma and IL-6 resulted in a reversal of the stimulatory effects due to IL-6. IFN-gamma and IL-1 had an additive inhibitory effect, whereas IFN-gamma and TNF-alpha acted in a synergistic fashion in inhibiting Epo production by Hep3B cells. The inhibitory effect of IFN-gamma appeared to be due to a down-modulation of Epo mRNA levels in CoCl2-treated Hep3B cells, as shown by Northern blot analysis. These data indicate that Epo production by hepatoma cells in vitro is inhibited by IFN-gamma, and that a complex network of interacting cytokines may regulate Epo production in response to an hypoxic stimulus. Overall, these results also suggest that IFN-gamma might have a role in the defective Epo production observed in several inflammatory and immunemediated disorders characterized by relatively high IFN-gamma plasma levels.
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PMID:Inhibition of erythropoietin production in vitro by human interferon gamma. 794 42

The addition of exogenous H2O2 inhibited hypoxia-induced erythropoietin (Epo) production in the human hepatoma cell line HepG2. Likewise, elevation of endogenous H2O2 levels by the addition of menadione or the catalase inhibitor, aminotriazole, dose-dependently lowered Epo production. The inhibitory effect of exogenous H2O2 on Epo formation could be completely overcome by co-incubation with catalase. When GSH levels in HepG2 cells were lowered, Epo production was more susceptible to H2O2-induced inhibition, indicating that H2O2 might affect thiol groups in regulatory proteins. Endogenous production of H2O2 in HepG2 cells was dependent on the pericellular O2 tension, being lowest under conditions of hypoxia. Our results support the hypothesis that an H2O2-generating haem protein might be part of the O2 sensor that controls Epo production. High H2O2 levels under conditions of normoxia suppress, whereas lower levels in hypoxic cells allow epo gene expression.
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PMID:Role of hydrogen peroxide in hypoxia-induced erythropoietin production. 798 Apr 10

The paraneoplastic syndrome of erythrocytosis is associated with a variety of neoplasms including renal adenocarcinoma, cerebellar hemangioma, and hepatoma. We now report the characterization of the biological and molecular features of an erythropoietin-secreting human renal adenocarcinoma, designated RCCEp+. Serial transplantation of the tumor in athymic mice resulted in a dramatic increase in hematocrit and serum erythropoietin concentration. Growth in vitro was accompanied by a constant rate of erythropoietin secretion. Karyotype analysis demonstrated several unusual features, including the absence of 3p deletions and near tetraploidy. Erythropoietin mRNA was demonstrated by Northern blot both in freshly excised tumor and in tumor cells growing in vitro. Erythropoietin secretion was constitutive and was not induced either by cobalt or hypoxia. Southern blot analysis revealed no rearrangement of the erythropoietin gene in the tumor. Interestingly, in situ hybridization demonstrated erythropoietin mRNA in only a small population of the tumor cells. Further studies of RCCEp+ should prove useful in elucidating the molecular basis for this paraneoplastic syndrome.
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PMID:Constitutive secretion of erythropoietin by human renal adenocarcinoma cells in vivo and in vitro. 798 67

Retinoic acid (RA) stimulated the production of erythropoietin (Epo) in a human hepatoma cell line, HepG2 cells. The stimulation was due to the accumulation of Epo mRNA. The Epo production in HepG2 cells was also dependent on O2 tension for cell culture but the enhancement of Epo production by RA was independent of O2 tension, indicating that RA exerts its effect through a pathway different from O2. Oral administration of RA to the vitamin A-depleted rats elevated the concentration of Epo in serum. These results suggest that RA up-regulates EPO production in vivo as well as in vitro.
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PMID:Retinoic acid up-regulates erythropoietin production in hepatoma cells and in vitamin A-depleted rats. 805 May 71


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